Monday, January 16, 2012

Langerhans scapegoats

Langerhans cells (LCs) residing in the epidermal layer of the skin represent a specialized dendritic cell subset. However, what is exactly their function is still a mystery. Even the development of mouse models specifically lacking LCs could not resolve the controversy. The new paper published in Science make this case even more confusing.

The study by Modi BG and Neustadter J, et al. (1), examined chemically-induced carcinogenesis model in mice lacking LCs. This particular mouse model lacks Langerhans cells due to langerin-driven diphtheria toxin A expression (langerin-DTA mouse). Any cells that will express langerin will be eliminated from the body. Because Langerhans cells express langerin they will be constitutively depleted. The authors showed that this mice were resistant to DMBA-TPA (carcinogens) induced skin papilloma development. Interestingly, this mice were resistant to DBMA-TPA induced papillomas even in absence of T cells. The authors showed that one way Langerhans cells were contributing to the papilloma development was through metabolism of DBMA into active DBMA-t-3, 4 diols. DBMA-t-3, 4 diol, in turn, had a mutagenic effect on keratinocyte DNA leading to papillomas. This mechanism was supported by observations that (a) Langerhans cells express enzymes capable of metabolizing DBMA and (b) application of DBMA-t-3, 4 diols induced papilloma development even in langerin-DTA mice (though direct application of DBMA-t-3, 4 diol induced low number of papillomas compared to DBMA). This may suggest that simple metabolism of DBMA into DBMA-t-3, 4 diol by Langerhans cells is not only mechanism by which Langerhans cells participate in tumorogenesis. In this regard, it is useful to keep in mind that Langerhans cells residence (maintenance) in skin is critically depended on the action of tumor-growth factor-β (TGF-β). It would be interesting to examine how absence of Langerhans cells affects the role of TGF-β in DBMA-TPA induced papilloma development.